Compounds

ABSTRACT

A compound of formula                    
     wherein 
     n is 0 or 1; m is 0 or 1; p is 0 or 1; X is oxygen or sulfur; Y is CH, N or NO; W is oxygen, H 2  or F 2 ; 
     A is N or C(R 2 ); G is N or C(R 3 ); D is N or C(R 4 ); 
     with the proviso that no more than one of A, G, and D is nitrogen, but at least one of Y, A, G, and D is nitrogen or NO; 
     R 1  is hydrogen or C 1  to C 4  alkyl; 
     R 2 , R 3 , and R 4  are independently hydrogen, halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, aryl, heteroaryl, OH, OC 1 -C 4  alkyl, CO 2 R 1 , —CN, —NO 2 , —NR 5 R 6 , —CF 3 , —OSO 2 CF 3  or R 2  and R 3 , or R 3  and R 4 , respectively, may together form another six membered aromatic or heteroaromatic ring sharing A and G, or G and D, respectively, containing between zero and two nitrogen atoms, and substituted with one to two of the following substituents: independently hydrogen, halogen, C 1 -C 4  alkyl, C 2 -C 4  alkenyl, C 2 -C 4  alkynyl, aryl, heteroaryl, OH, OC 1 -C 4  alkyl, CO 2 R 1 , —CN, —NO 2 , —NR 5 R 6 , —CF 3 , —OSO 2 CF 3 ; R 5  and R 6  are independently hydrogen, C 1 -C 4  alkyl, C(O)R 7 , C(O)NHR 8 , C(O)OR 9 , SO 2 R 10  or may together be (CH 2 ) j Q(CH 2 ) k  where Q is O, S, NR 11 , or a bond; j is 2 to 7, k is 0 to 2; R 7 , R 8 , R 9 , R 10 , and R 11  are independently C 1 -C 4  alkyl, aryl, or heteroaryl, or an enantiomer thereof, 
     and the pharmaceutically acceptable salts thereof, processes for preparing them, composition containing them, and their use in therapy, especially in the treatment or prophylaxis of psychotic disorders and intellectual impairment disorders.

This is a divisional of application Ser. No. 09/171,983, filed Oct. 29,1998, now U.S. Pat. No. 6,110,914, the entire content of which is herebyincorporated by reference in this application.

TECHNICAL FIELD

This invention relates to novel spiroazabicyclic heterocyclic amines orpharmaceutically acceptable salts thereof, processes for preparing them,pharmaceutical compositions containing them and their use in therapy. Afurther object is to provide active compounds which are potent ligandsfor nicotinic acetylcholine receptors (nAChR's).

BACKGROUND OF THE INVENTION

The use of compounds which bind nicotinic acetylcholine receptors in thetreatment of a range of disorders involving reduced cholinergic functionsuch as Alzheimer's disease, cognitive or attention disorders, anxiety,depression, smoking cessation, neuroprotection, schizophrenia,analgesia, Tourette's syndrome, and Parkinson's disease has beendiscussed in McDonald et al. (1995) “Nicotinic Acetylcholine Receptors:Molecular Biology, Chemistry and Pharmacology”, Chapter 5 in AnnualReports in Medicinal Chemistry, vol. 30, pp. 41-50, Academic Press Inc.,San Diego, Calif.; and in Williams et al. (1994) “Neuronal NicotinicAcetylcholine Receptors,” Drug News & Perspectives, vol. 7, pp. 205-223.

U.S. Pat. No. 5,468,875 discloses N-alkylcarbamic acid1-azabicyclo[2.2.1]hept-3-yl esters which are centrally activemuscarinic agents useful in the treatment of Alzheimer's disease andother disorders.

N-(2-alkoxyphenyl)carbamic acid 1-azabicyclo[2.2.2]octan-3-yl esters aredisclosed in Pharmazie, vol. 48, 465-466 (1993) along with their localanesthetic activity. N-phenylcarbamic acid 1-azabicyclo[2.2.2]octan-3-ylesters substituted at the ortho position on the phenyl ring aredescribed as local anaesthetics in Acta Pharm. Suecica, 7, 239-246(1970).

Furopyridines useful in controlling synaptic transmission are disclosedin WO 97/05139.

DISCLOSURE OF THE INVENTION

According to the invention it has been found that a compound of formulaI

wherein

n is 0 or 1;

m is 0 or 1;

p is 0 or 1;

Y is CH, N or NO

X is oxygen or sulfur;

W is oxygen, H₂ or F₂;

A is N or C(R²);

G is N or C(R³);

D is N or C(R⁴);

with the proviso that no more than one of A, G, and D is nitrogen but atleast one of Y, A, G, and D is nitrogen or NO;

R¹ is hydrogen or C₁-C₄ alkyl;

R², R³, and R⁴ are independently hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, aryl, heteroaryl, OH, OC₁-C₄ alkyl, CO₂R¹, —N,—NO₂, —NR⁵R⁶, —CF₃, —OSO₂CF₃, or R² and R³, or R³ and R⁴, respectively,may together form another six membered aromatic or heteroaromatic ringsharing A and G, or G and D, respectively containing between zero andtwo nitrogen atoms, and substituted with one to two of the followingsubstituents: independently hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, aryl, heteroaryl, OH, OC₁-C₄ alkyl, CO₂R¹, —CN,—NO₂, —NR⁵R⁶, —CF₃, OSO₂CF₃;

R⁵ and R⁶ are independently hydrogen, C₁-C₄ alkyl, C(O)R⁷, C(O)NHR⁸,C(O)OR⁹, SO₂R¹⁰ or may together be (CH₂)_(j)Q(CH₂)_(k) where Q is O, S,NR¹¹, or a bond;

j is 2 to 7;

k is 0 to 2;

R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are independently C₁-C₄ alkyl, aryl, orheteroaryl, or an enantiomer thereof, and the pharmaceuticallyacceptable salts thereof is a potent ligand for nicotinic acetylcholinereceptors.

Unless otherwise indicated, the C₁-C₄ alkyl groups referred to herein,e.g., methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, t-butyl,s-butyl, may be straight-chained or branched, and the C₃-C₄ alkyl groupsmay also be cyclic, e.g., cyclopropyl, cyclobutyl.

Unless otherwise indicated, the C₁-C₆ alkyl groups referred to herein,e.g., methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, t-butyl,s-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl, or i-hexylmay be straight-chained or branched, and the C₃-C₆ alkyl groups may alsobe cyclic, e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Unless otherwise indicated, the C₁-C₄ alkoxy groups referred to herein,e.g., methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,t-butoxy, s-butoxy, may be straight-chained or branched.

Unless otherwise indicated, the C₂-C₄ alkenyl groups referred to hereinmay contain one or two double bonds, e.g., ethenyl, i-propenyl,n-butenyl, i-butenyl, allyl, 1,3-butadienyl.

Unless otherwise indicated, the C₂-C₄ alkynyl groups referred to hereincontain one triple bond, e.g., ethynyl, propynyl, 1- or 2-butynyl.

Halogen referred to herein may be fluoride, chloride, bromide, oriodide.

Unless otherwise indicated, aryl refers to a phenyl ring optionallysubstituted with one to three of the following substituents: hydrogen,halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, OH, OC₁-C₄ alkyl,CO₂R¹, —CN, —NO₂, —NR⁵R⁶, —CF₃;

Unless otherwise indicated, heteroaryl refers to a five- or six-memberedaromatic ring containing one or two nitrogen atoms, such as pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl or pyrazolyl,with the carbon atoms of that ring optionally substituted with one tothree of the following substituents: hydrogen, halogen, C₁-C₄ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, OH, OC₁-C₄ alkyl, CO₂R¹, —CN, —NO₂,—NR⁵R⁶, —CF₃; R⁵ and R⁶ may together be (CH₂)_(j)Q(CH₂)_(k) where Q isO, S, NR¹¹, or a bond, and where j is 2 to 7, preferably 2 to 3, and kis 0 to 2, so as to form a 3-7 membered ring, preferably a 5- or6-membered ring, for example pyrrolidinyl, imidazolidinyl piperazinyl,piperidyl, morpholinyl, or thiomorpholinyl.

R² and R³ may together form another six membered aromatic orheteroaromatic ring sharing A and G containing between zero and twonitrogen atoms refers to groups such as quinoline, 1,5-, 1,6-, 1,7-, or1,8-diazanaphthalene.

R³ and R⁴ may together form another six membered aromatic orheteroaromatic ring sharing G and D containing between zero and twonitrogen atoms refers to groups such as soquinoline, 2,5-, 2,6-, 2,7-,or 2,8-diazanaphthalene.

Preferred compounds of the invention are compounds of formula I whereinm is 1; n is 0; p is 0; X is oxygen; W is H₂; A is C(R²) ; G is C(R³) ;D is C(R⁴).

Preferred compounds of the invention include the following:

spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-phenylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-nitrospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

1′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]isoquinoline];

5′-(phenylcarboxamido)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-(phenylaminocarbonylamino)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-(phenylsulfonylamido)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-N-methylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-N,N-dimethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-N,N-diethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-N-ethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-N-benzylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-N-formamidospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-N-acetamidospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]isoquinoline];

spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]quinoline];

5′-ethenylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-(E)-(phenylethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-(4-morpholino)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-(1-azetidinyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-(E)-(2-(4-pyridyl)ethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-(E)-(2-(2-pyridyl)ethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-(2-trimethylsilylethynyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3b]pyridine];

5′-ethynylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-(2-furyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-(3-pyridyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-methylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine-5′carbonitrile];

spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine-5′carboxamide];

5′-N′-(3-chlorophenyl)aminocarbonylminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-N′-(2-nitrophenyl)aminocarbonylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

4′-methoxyspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

4′-phenylthiospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

4′-(N-2-aminoethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

4′-phenylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

4′-methylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

4′-(4-N-methylpiperazin-1-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

4′-chloro-spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[3,2-c]pyridine];

spiro[-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[3,2-c]pyridine];

spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine-7′-oxide];

spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine-6′-carbonitrile];

6′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];

6′-fluorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];

and the enantiomers, and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of the invention are compounds offormula I wherein m is 1; n is 0; p is 0; X=oxygen; W is H₂; A=CH, D=CH,and G=C(R3), including the foUowing compounds:

spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine-7′-oxide];

5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-phenylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-nitrospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-(phenylcarboxamido)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-(phenylaminocarbonylamino)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-(phenylsulfonylamido)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-N-methylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-N,N-dimethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-N,N-diethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-N-ethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-N-benzylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-N-formamidospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-N-acetamidospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-ethenylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-(E)-(phenylethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-(4-morpholino)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-(1-azetidinyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-(E)-(2-(4-pyridyl)ethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-(E)-(2-(2-pyridyl)ethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-(2-trimethylsilylethynyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-ethynylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-(2-furyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyrdine];

5′-(3-pyridyl)spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

5′-methylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine];

spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine-5′carbonitrile];

spiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)furo[2,3-b]pyridine-5′carboxamide];

5′-N′-(3-chlorophenyl)aminocarbonylminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

5′-N′-(2-nitrophenyl)aminocarbonylaminospiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridine];

Methods of Preparation

In the reaction schemes and text that follow, A, G, D, X, W, Y, Z, m, n,and p, unless otherwise indicated, are as defined above for formula I.

(A) Compounds wherein p is 0 and Y is N

The compounds of formula I, wherein p is 0 and Y is N, may be preparedaccording to the methods outlined in Scheme I.

Compounds of formula I where W=H₂ and p is 0 may be prepared from thedeprotection of a compound of formula IIA using acid in a suitablesolvent. Suitable acids include mineral, organic and Lewis acids, forexample, hydrochloric and hydrobromic acid, sulfuric acid, triflic acid,methanesulfonic acid, and boron trifluoride etherate. The preferred acidis hydrobromic acid. Suitable solvents include acetone, butanone,ethanone, and pinacolone. The preferred solvent is acetone. The reactionis usually conducted at a temperature from about −10° C. to about 100°C., preferably about 0° C. to about 60° C. Alternatively thedeprotection may be conducted by heating the borane complex in alcoholicsolvents. A preferred method is by refluxing a ethanolic solution of thecomplex.

Compounds of formula I where W=O (oxygen) and p is 0 may be prepared bythe oxidation of compounds of formula IIA, for example using seleniumdioxide, or by reaction first with N-bromosuccinimide then with sodiumbicarbonate and methylsulfoxide, followed by removal of the borane groupas described above.

Compounds of formula I where W=F₂ and p is 0 may be prepared fromcompounds of formula I where W=O by reaction with a fluorinating agent,for example diethylaminosulfur trifluoride.

Compounds of formula IIA may be prepared from the cyclization of acompound of formula III wherein L is fluoro, chloro, bromo, iodo, —OCH₃,—SPh, —SCH₃, —SO₂Ph, or —SO₂CH₃ in the presence of a base in an inertsolvent. Suitable bases include sodium hydride, sodium amide, potassiumhydride, potassium t-amylate, potassium t-butoxide, and potassiumbis(trimethylsilyl)amide. The preferred base is sodium hydride. Suitableinert solvents include N,N-dimethylformamide, N-methylpyrrolidin-2-one,ethers such as diethyl ether, tetrahydrofuran, and 1,4-dioxane, anddimethylsulfoxide. The preferred inert solvent is N,N-dimethylformamide.The reaction is usually conducted at a temperature from about 10° C. toabout 100° C., preferably about 20° C. to about 66° C.

Compounds of formula III wherein L is fluoro, chloro, bromo, iodo,—OCH₃, —SPh, —SCH₃, —SO₂Ph, or —SO₂CH₃ may be prepared by the reactionof a compound of formula IV with a compound of formula V wherein L isdefined as above in an inert solvent. Suitable inert solvents includediethyl ether, tetrahydrofuran and 1,4-dioxane. The preferred inertsolvent is tetrahydrofuran. The reaction is usually conducted at atemperature from about −100° C. to about 0° C., preferably about −78° C.to about −25° C.

Compounds of formula V wherein L is defined as above may be preparedfrom a compound of formula VIII wherein L is defined as above using alithium base and a proton transfer agent in an inert solvent. Suitablelithium bases include lithium diisopropylamide, n-butyllithium,sec-butyllithium, tert-butyllithium, and phenyllithium. The preferredlithium base is phenyllithium. Suitable proton transfer agents includehindered secondary amines such as diisopropylamine and2,2,6,6-tetramethylpiperidine. The preferred proton transfer agent isdiisopropylamine. Suitable inert solvents include diethyl ether,tetrahydrofuran and 1,4-dioxane. The preferred inert solvent istetrahydrofuran. The reaction is usually conducted at a temperature fromabout −100° C. to about 0° C., preferably about −78° C. to about −25° C.Compounds of formula V are usually taken directly into the reaction withcompounds of formula IV without purification.

Compounds of formula IV may be prepared from the reaction of a compoundof formula VI with borane (BH₃ or B₂H₆) in an inert solvent. Borane intetrahydrofuran is preferred. Suitable inert solvents include diethylether, tetrahydrofuran and 1,4dioxane. The preferred inert solvent istetrahydrofuran. The reaction is usually conducted at a temperature fromabout −10° C. to about 66° C., preferably about 0° C. to about 20° C.

Compounds of formula VIII are known, e.g., either commercially availableor may be prepared by methods known to one skilled in the art (see e.g,The Chemistry of Heterocyclic Compounds, Pyridine and Its Derivatives,Part 1, E. Klingsberg, Ed., Interscience Publishers, Inc, NY, 1960).

Compounds of formula VI may be prepared from compounds of formula VII bymethods known to one skilled in the art. For example, compounds offormula VI wherein X represents oxygen may be prepared from thecorresponding compound of formula VII wherein X represents the oxygen ofa ketone using one of the reagents well known in the art for preparationof oxiranes from ketones (see e.g. the reactions referenced in J. March,“Advanced Organic Chemistry” (1985) 3rd Edition, page 1161). Compoundsof formula VI wherein X represents sulfur may be prepared from thecorresponding compound of formula VII wherein X represents either oxygenor sulfur using one of the methods well known in the art for preparationof episulfides from ketones or thioketones (see, e.g. the reactionsreferenced in J. March, “Advanced Organic Chemistry” (1985) 3rd Edition,pages 866-867).

Compounds of formula VII are known, e.g., either commercially availableor may be prepared by methods known to one skilled in the art (see, e.g,The Chemistry of Heterocyclic Compounds, Heterocyclic Systems withBridgehead Nitrogen Atoms, Part 2, W. L. Mosby, Ed., IntersciencePublishers, Inc, NY, 1961).

(B) Compounds wherein p is 1 and Y is N

The compounds of formula I (p=1) may be prepared according to themethods described in Scheme II or Scheme II, below.

Compounds of formula I where W is H₂ and p is 1 may be prepared from thedeprotection of a compound of formula IX using acid in a suitablesolvent. Suitable acids include mineral, organic and Lewis acids, forexample, hydrochloric and hydrobromic acid, sulfuric acid, triflic acid,methanesulfonic acid and borontrifluoride etherate. The preferred acidis hydrobromic acid. Suitable solvents include acetone, butanone,ethanone, and pinacolone. The preferred solvent is acetone. The reactionis usually conducted at a temperature from about −10° C. to about 100°C., preferably about 0° C. to about 60° C. Alternatively thedeprotection may be conducted by heating the borane complex in alcoholicsolvents. A preferred method is by refluxing a ethanolic solution of thecomplex.

Compounds of formula I where W=O and p is 1 may be prepared by theoxidation of compounds of formula I, where W is H₂ and p is 1, usingselenium dioxide, or by reaction first with N-bromosuccinimide then withsodium bicarbonate and methylsulfoxide, followed by removal of theborane group as described above.

Compounds of formula I, where W=F₂ and p is 1, may be prepared fromcompounds of formula I, where W=O and p is 1, by reaction withdiethylaminosulfur trifluoride.

Compounds of formula IX may be prepared from the cyclization of acompound of formula X wherein L is fluoro, chloro, bromo, iodo, —OCH₃,—SPh, —SCH₃, —SO₂Ph, or —SO₂CH₃ in the presence of a base in an inertsolvent. Suitable bases include sodium hydride, sodium amide, potassiumhydride, potassium t-amylate, potassium t-butoxide, and potassiumbis(trimethylsilyl)amide. The preferred base is sodium hydride. Suitableinert solvents include N,N-dimethylformamide, N-methylpyrrolidin-2-one,ethers such as diethyl ether, tetrahydrofuran, and 1,4-dioxane, anddimethylsulfoxide. The preferred inert solvent is N,N-dimethylformamide.The reaction is usually conducted at a temperature from about −10° C. toabout 100° C., preferably about 20° C. to about 66° C.

Compounds of formula X wherein L is fluoro, chloro, bromo, iodo, —OCH₃,—SPh, —SCH₃, —SO₂CH₃ may be prepared by the reaction of a compound offormula XI with a compound of formula V wherein L is defined as above inan inert solvent. Suitable inert solvents include diethyl ether,tetrahydrofuran and 1,4-dioxane. The preferred inert solvent istetrahydrofuran. The reaction is usually conducted at a temperature fromabout −100° C. to about 0° C., preferably about −78° C. to about −25° C.

Compounds XI, wherein P is —SO₂Ph, —SO₂PhCH₃-4, —SO₂CH₃ or —SO₂CF₃ maybe prepared from compounds XII by reaction with a reagent such astoluenesulfonyl chloride, methanesulfonyl chloride, ortrifluoromethanesulfonyl chloride in the presence of an amine base suchas triethylamine, dimethylaminopyridine, or diazabicyclo[4.3.0]nonane inan inert solvent. Suitable inert solvents may be dichloromethane,chloroform, tetrahydrofuran, diethyl ether, or dioxane. The preferredinert solvent is dichloromethane. The reaction is usually conducted at atemperature from about −10° C. to about 66° C., preferably about 0° C.to about 20° C.

Compounds XII may be prepared from compounds of formula XIII byreduction with reagents such as lithium aluminum hydride, sodiumbis(2-methoxyethoxy)aluminum hydride, sodium or lithium triethylboride,lithium tri-sec-butylborohydride, potassium tri-sec-butylborohydride,sodium tri-sec-butylborohydride or lithium borohydride. The preferredreagent is lithium borohydride. Suitable inert solvents include diethylether, tetrahydrofuran and 1,4-dioxane. The preferred inert solvent istetrahydrofuran. The reaction is usually conducted at a temperature fromabout −78° C. to about 66° C., preferably about −10° C. to about 20° C.

Compounds of formula XIII, wherein R is C₁-C₆ alkyl, —CH₂—Ar, or Ar,where Ar is phenyl optionally substituted with one to three of thefollowing substitutents: halogen, C₁-C₄ alkyl, or C₁-C₄ alkoxy, may beprepared from the reaction of a compound of formula XIV with borane (BH₃or B₂H₆) in an inert solvent. Borane in tetrahydrofuran is preferred.Suitable inert solvents include diethyl ether, tetrahydrofuran and1,4-dioxane. The preferred inert solvent is tetrahydrofuran. Thereaction is usually conducted at a temperature from about −10° C. toabout 66° C., preferably about 0° C. to about 20° C.

Compounds of formula XIV are known, e.g., either commercially availableor may be prepared from compounds of formula VII by methods known to oneskilled in the art for the preparation of β-hydroxy esters from thereaction of esters and ketones (see, e.g. the reactions referenced in J.March, “Advanced Organic Chemistry” (1985) 3rd Edition, page 439).

Compounds of formula I where W is H₂ and p is 1 may be prepared from thecyclization of a compound of formula XVIII wherein L is fluoro, chloro,bromo, iodo, —OCH₃, —SPh, —SCH₃, —SO₂Ph, or —SO₂CH₃ in the presence of abase in an inert solvent. Suitable bases include sodium hydride, sodiumamide, potassium hydride, potassium t-amylate, potassium t-butoxide, andpotassium bis(trimethylsilyl)amide. The preferred base is sodiumhydride. Suitable inert solvents include N,N-dimethylformamide,N-methylpyrrolidin-2-one, ethers such as diethyl ether, tetrahydrofuran,and 1,4-dioxane, and dimethylsulfoxide. The preferred inert solvent isN,N-dimethylformamide. The reaction is usually conducted at atemperature from about −10° C. to about 100° C., preferably about 20° C.to about 66° C.

Compounds of formula XVIII wherein L is defined as above may be preparedby catalytic hydrogenation of a compound of formula XVII using catalystssuch as palladium on carbon, palladium hydroxide on carbon, palladiumoxide, platinum on carbon, platinum oxide, Raney nickel, or rhenium oncarbon in an inert solvent. Suitable inert solvents include methanol,ethanol, aqueous methanol or ethanol and ethyl acetate. The preferredsolvent is ethanol. The reaction is usually conducted at a temperaturefrom about 0° C. to about 100° C., preferably about 20° C. to about 50°C.

Compounds of formula XVII wherein L is defined as above may be preparedby reaction of a compound of formula XV with a compound of formula XVIusing a palladium catalyst together with a suitable ligand, base, andsolvent. Suitable palladium catalysts include palladium acetate.Suitable ligands include phosphine ligands, such as triphenylphosphineor tri-o-tolylphosphine. Suitable bases include amines and inorganicbases, such as triethyl amine, diisopropylethylamine, sodium carbonateor tetrabutylammonium acetate. Suitable solvents includedimethylformamide or acetonitrile. The reaction is usually conducted ata temperature from about 0° C. to about 140° C., preferably about 20° C.to about 85° C.

Compounds of formula XVI, where L is defined as above and R² is chloro,bromo, iodo, fluoro, trifluoromethylsulfonyl, toluenesulfonyl ormethylsulfonyl may be prepared by literature methods from commerciallyavailable materials.

Compounds of formula XV may be prepared from compounds of formula VII bymethods known to one skilled in the art for the preparation of allylalcohols from ketones using vinylmetal salts such as vinylmagnesiumbromide.

(C) Compounds wherein p is 0 or 1

Compounds of formula I wherein R², R³, or R⁴ is halogen may be preparedfrom compounds of formula I wherein the corresponding substituent ishydrogen by reaction with a suitable halogenating agent, for examplebromine in acetic acid. The transformation may require the addition ofan acidic catalyst, such as the corresponding iron trihalide.

Compounds of formula I wherein R², R³, or R⁴ is C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, aryl, heteroaryl may be prepared from compoundsof formula I wherein the corresponding substituent is halogen or OSO₂CF₃by reaction with an appropriate alkyl, alkenyl, alkynyl, aryl orheteroaryl stannane reagent, in the presence of a suitableorganometallic catalyst, for exampletetrakis(triphenylphosphine)palladium (0), in a suitable solvent, forexample 1,2-dimethoxyethane.

Compounds of formula I wherein R², R³, or R⁴ is aryl, heteroaryl may beprepared from compounds of formula I wherein the correspondingsubstituent is halogen or OSO₂CF₃ by reaction with an aryl or heteroarylboronic acid, in the presence of a suitable organometallic catalyst, forexample tetrakis(triphenylphosphine)palladium (0), in a suitablesolvent, for example 1,2-dimethoxyethane.

Compounds of formula I wherein R², R³, or R⁴ is NO₂ may be prepared fromcompounds of formula I wherein the corresponding substituent is hydrogenby nitration using a suitable nitrating agent, for example nitric acidin concentrated sulfuric acid.

Compounds of formula I wherein R², R³, or R⁴ is NH₂ may be prepared fromcompounds of formula I wherein the corresponding substituent is NO₂ byreduction using a suitable procedure, for example hydrogenation.Hydrogenation may be performed by the reaction of a compound, dissolvedin a suitable solvent, with gaseous hydrogen in the presence of asuitable catalyst. Suitable solvents include methanol, ethanol, andacetic acid. Suitable catalysts include palladium, for example as 10%palladium on carbon.

Compounds of formula I wherein R², R³, or R⁴ is NR⁵R⁶ wherein R⁶ isalkyl may be prepared from compounds of formula I wherein thecorresponding substituent is NHR5 by a suitable alkylation procedure.Also, compounds of formula I wherein R², R³, or R⁴ is NR⁵R⁶ wherein R⁵and R⁶ are identical alkyl groups or R⁵ and R⁶ together are(CH₂)_(j)Q(CH₂)_(k) may be prepared from compounds of formula I whereinthe corresponding substituent is NH₂ by a suitable alkylation procedure.Suitable alkylation procedures may include treatment with a suitablealkyl halide or sulfonate ester and base, for example sodium hydride, ina suitable solvent, for example DMF, or treatment with a suitablealdehyde or ketone in the presence of an acidic catalyst, for examplezinc chloride, a reducing agent, for example sodium cyanoborohydride,and solvent, for example ethanol.

Compounds of formula I wherein R², R³, or R⁴ is OSO₂CF₃ may be preparedfrom compounds of formula I wherein the corresponding substituent is OHby reaction with trifluoromethanesulfonic anhydride in the presence of asuitable base, for example 2,6-di-t-butylpyridine, in a suitablesolvent, for example dichloromethane.

Compounds of formula I wherein R², R³, or R⁴ is NR⁵R⁶ may also beprepared from compounds of formula I wherein the correspondingsubstituent is halide or OSO₂CF₃ by substitution with the appropriateamine NHR⁵R⁶. Suitable procedures include nucleophilic displacement,involving treatment with the amine, in excess or in the presence of anadded base, and a suitable solvent, for example DMSO, or organometalliccomplex catalysed substitution, involving treatment with the amine inthe presence of a suitable organometallic complex, for example complexesof palladium with chelating phosphine ligands, as described in J. Org.Chem., 1996, vol. 61, pp. 7240.

Compounds of formula I wherein R², R³, or R⁴ is NR⁵C(O)R⁷ may beprepared from compounds of formula I wherein the correspondingsubstituent is NH₂ by a suitable acylation procedure. Suitable acylationprocedures include treatment with a carboxylic acid chloride R⁶C(O)Cl inthe presence of an optional nucleophilic catalyst, such as4-(N,N-dimethylamino)pyridine, a base, for example pyridine ortriethylamine, and a suitable solvent, for example tetrahydrofuran, or,alternatively, treatment with a carboxylic acid R₆C(O)OH with a couplingagent, for example 1,3-dicyclohexylcarbodiimide, in a suitable solvent,for example tetrahydrofuran.

Compounds of formula I wherein R², R³, or R⁴ is NR⁵C(O)NHR⁸ may beprepared from compounds of formula I wherein the correspondingsubstituent is NHR⁵ by treatment with the appropriate isocyanate R⁸NCOin a suitable solvent, for example tetrahydrofuran.

Compounds of formula I wherein R², R³, or R⁴ is NR⁵C(O)OR⁹ may beprepared from compounds of formula I wherein the correspondingsubstituent is NHR⁵ by treatment with an appropriate oxychloride orcarbonate in the presence of an optional nucleophilic catalyst, such as4-(N,N-dimethylamino)pyridine, a base, for example pyridine ortriethylamine, and a suitable solvent, for example tetrahydrofuran.

Compounds of formula I wherein R², R³, or R⁴ is NR⁵SO₂R¹⁰ may beprepared from compounds of formula I wherein the correspondingsubstituent is NHR⁵ by treatment with an appropriate sulfonyl chloridein a suitable solvent, such as pyridine.

Compounds of formula I wherein R², R³, or R⁴ is CN may be prepared fromcompounds of formula I wherein the corresponding substituent is halideor OSO₂CF₃ by reaction with a cyanide salt, in a suitable solvent, withthe addition of a suitable catalyst possibly also being required.Suitable cyanide salts include copper (I) cyanide, sodium cyanide,sodium dicyanocuprate, or potassium cyanide, and suitable solventsinclude N,N-dimethylformamide, dimethylsulfoxide, or pyridine. Catalystswhich may facilitate the transformation include copper (I) oxide,tetrakis(triphenylphosphine)palladium (0), or nickel (0) complexesgenerated in situ from dibromobis(triphenylphosphine)nickel(ii), zincand triphenylphosphine.

Compounds of formula I wherein R², R³ or R⁴ is OH, OC₁-C₄ alkyl may beprepared either from an appropriately substituted 2-chloropyridine orvia chemical transformation from another substituent e.g; the OHderivative from the NH₂ via the diazo intermediate.

Where necessary, hydroxy, amino, or other reactive groups may beprotected using a protecting group as described in the standard text“Protecting Groups in Organic Synthesis”, 2^(nd) Edition (1991) byGreene and Wuts.

Compounds of Formula I may be prepared from other compounds of Formula Iby using general methods known to one skilled in the art forinterconversion of functional groups, (see, e.g. the reactionsreferenced in J. March, “Advanced Organic Chemistry” (1985) 3rdEdition).

Also, several of the substituted compounds of Formula I may be preparedby using an appropriately substituted compound of Formula VIII, viz.,2-chloro-5-trifluoromethylpyridine would yield the R³ is CF₃.

The above described reactions, unless otherwise noted, are usuallyconducted at a pressure of about one to about three atmospheres,preferably at ambient pressure (about one atmosphere). Unless otherwisestated, the above described reactions are conducted under an inertatmosphere, preferably under a nitrogen atmosphere.

The compounds of the invention and intermediates may be isolated fromtheir reaction mixtures by standard techniques.

Acid addition salts of the compounds of formula I which may be mentionedinclude salts of mineral acids, for example the hydrochloride andhydrobromide salts; and salts formed with organic acids such as formate,acetate, maleate, benzoate, tartrate, and fumarate salts.

Acid addition salts of compounds of formula I may be formed by reactingthe free base or a salt, enantiomer or protected derivative thereof,with one or more equivalents of the appropriate acid. The reaction maybe carried out in a solvent or medium in which the salt is insoluble orin a solvent in which the salt is soluble, e.g., water, dioxane,ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents,which may be removed in vacuum or by freeze drying. The reaction may bea metathetical process or it may be carried out on an ion exchangeresin.

The compounds of formula I exist in tautomeric or enantiomeric forms,all of which are included within the scope of the invention. The variousoptical isomers may be isolated by separation of a racemic mixture ofthe compounds using conventional techniques, e.g. fractionalcrystallization, or chiral HPLC. Alternatively the individualenantiomers may be made by reaction of the appropriate optically activestarting materials under reaction conditions which will not causeracemization.

(D) Compounds wherein Y is NO

Compounds of formula I, wherein Y is NO, X is oxygen, A is C(R²), G isC(R³) and D is C(R⁴), may be prepared from compounds of formula XIX,wherein X is oxygen, A is C(R²), G is C(R³) and D is C(R⁴), by reductionwith a suitable reducing agent under suitable conditions, for examplesulfur dioxide in ethanol at ambient temperature.

Compounds of formula XIX may be prepared from compounds of formula Iwherein Y is N, X is oxygen, A is C(R²), G is C(R³) and D is C(R⁴), byoxidation with a suitable oxidising agent under suitable conditions, forexample aqueous hydrogen peroxide in acetic acid at reflux temperature.

Compounds of the formula I wherein Y is N, X is oxygen, A is C(R²), G isC(R³) and D is C(R⁴), may be prepared in analogy with sections (A), (B)and (C), above.

Compounds of formula I, in which Y is N and A is C(R²), wherein R² ishydroxyl, may be prepared from compounds of formula I in which Y is NOby rearrangement using a carboxylic anhydride in a suitable solvent, forexample trifluoroacetic anhydride in DMF;

Compounds of formula I in which Y is N and A is C(R²), wherein R² ishalogen, may be prepared from compounds of formula I in which Y is NOand A is C(R²), wherein R² is hydrogen, by reaction with a phosphorushalide or oxyhalide, either neat or with a suitable co-solvent, forexample neat phosphorus oxychloride.

Compounds of formula I in which Y is N and A is C(R²), wherein R² is CN,may be prepared from compounds of formula I in which Y is NO and A isC(R²), wherein R² is hydrogen, by reaction with a suitable cyanidesource such as trimethylsilyl cyanide in the presence of a suitablebase, for example triethylamine, in a suitable solvent, for exampleacetonitrile.

Intermediates

A further aspect of the invention relates to new intermediates. Specialinterest among these new intermediates are the borane containingcompounds, especially the compound of formula I in Scheme I and thecompound of formula XIII in Scheme II. These intermediates are useful inthe synthesis of compounds of formula I, but their use is not limited tothe synthesis of said compounds;

Thus, compounds of the formula II

wherein

n is 0 or 1;

m is 0 or 1;

p is 0 or 1;

X is oxygen or sulfur;

W is oxygen, H₂ or F₂;

A is N or C(R²);

G is N or C(R³);

D is N or C(R⁴);

with the proviso that no more than one of A, G, and D is nitrogen;

R¹ is hydrogen or C₁-C₄ alkyl;

R², R³, and R⁴ are independently hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, aryl, heteroaryl, OH, OC₁-C₄ alkyl CO₂R¹, —CN,—NO₂, —NR⁵R⁶, —CF₃, —OSO₂CF₃ or R² and R³, or R³ or R⁴, respectively,may together form another six membered aromatic or heteroaromatic ringsharing A and G, or G and D, respectively, containing between zero andtwo nitrogen atoms, and substituted with one to two of the followingsubstituents: independently hydrogen, halogen, C₁-C₄ alkyl, C₂-C₄alkenyl, C₂-C₄ alkynyl, aryl, heteroaryl, OH, OC₁-C₄ alkyl, CO₂R₁, —CN,—NO₂, —NR⁵R⁶, —CF₃, —OSO₂CF₃;

R⁵ and R⁶ are independently hydrogen, C₁-C₄ alkyl, C(O)R⁷, C(O)NHR⁸,C(O)OR⁹, SO₂R¹⁰ or may together be (CH₂)_(j)Q(CH₂)_(k) where Q is O, S,NR¹¹, or a bond;

j is 2 to 7;

k is 0 to 2;

R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are independently C₁-C₄ alkyl, aryl, orheteroaryl,

or an enantiomer thereof.

Compounds of formula XIII

wherein

n is 0 or 1;

m is 0 or 1;

X is oxygen or sulfur;

R¹ is hydrogen or C₁ to C₄ alkyl;

R is C₁-C₆ alkyl, —CH₂—Ar, or Ar;

Ar is phenyl optionally substituted with one to three of the followingsubstitutents: halogen, C₁-C₄ alkyl, or C₁-C₄ alkoxy,

or an enantiomer thereof.

Intermediate compounds also exist in enantiomeric forms and may be usedas purified enantiomers, racemates or mixtures.

Use of compounds IV, III, II, XIII, X and IX as intermediates in asynthesis of a ligand for nicotinic acetylcholine receptors is anotheraspect of the invention.

A further aspect of the invention relates to the utility of compounds offormula I wherein Y is NO as intermediates. These intermediates areuseful in the synthesis of compounds of formula I wherein Y is N, buttheir use is not limited to the synthesis of said compounds.

Pharmaceutical Compositions

A further aspect of the invention relates to a pharmaceuticalcomposition for treating or preventing a condition or disorder asexemplified below arising from dysfunction of nicotinic acetylcholinereceptor neurotransmission in a mammal, preferably a human, comprisingan amount of a compound of formula I, an enantiomer thereof or apharmaceutically acceptable salt thereof, effective in treating orpreventing such disorder or condition and an inert pharmaceuticallyacceptable carrier.

For the above-mentioned uses the dosage administered will, of course,vary with the compound employed, the mode of administration and thetreatment desired. However, in general, satisfactory results areobtained when the compounds of the invention are administered at a dailydosage of from about 0.1 mg to about 20 mg per kg of animal body weight,preferably given in divided doses 1 to 4 times a day or in sustainedrelease form. For man, the total daily dose is in the range of from 5 mgto 1,400 mg, more preferably from 10 mg to 100 mg, and unit dosage formssuitable for oral administration comprise from 2 mg to 1,400 mg of thecompound admixed with a solid or liquid pharmaceutical carrier ordiluent.

The compounds of formula I, or an enantiomer thereof, andpharmaceutically acceptable salts thereof, may be used on their own orin the form of appropriate medicinal preparations for enteral orparenteral administration. According to a further aspect of theinvention, there is provided a pharmaceutical composition includingpreferably less than 80% and more preferably less than 50% by weight ofa compound of the invention in admixture with an inert pharmaceuticallyacceptable diluent or carrier.

Examples of diluents and carriers are:

for tablets and dragees: lactose, starch, talc, stearic acid; forcapsules: tartaric acid or lactose;

for injectable solutions: water, alcohols, glycerin, vegetable oils; forsuppositories: natural or hardened oils or waxes.

There is also provided a process for the preparation of such apharmaceutical composition which comprises mixing the ingredients.

Utility

A further aspect of the invention is the use of a compound according tothe invention, an enantiomer thereof or a pharmaceutically acceptablesalt thereof, in the manufacture of a medicament for the treatment orprophylaxis of one of the below mentioned diseases or conditions; and amethod of treatment or prophylaxis of one of the above mentioneddiseases or conditions, which comprises administering a therapeuticallyeffective amount of a compound according to the invention, or anenantiomer thereof or a pharmaceutically acceptable salt thereof, to apatient.

Compounds according to the invention are agonists of nicotinicacetylcholine receptors. While not being limited by theory, it isbelieved that agonists of the α7 nAChR (nicotinic acetylcholinereceptor) subtype should be useful in the treatment or prophylaxis ofpsychotic disorders and intellectual impairment disorders, and haveadvantages over compounds which are or are also agonists of the α4 nAChRsubtype. Therefore, compounds which are selective for the α7 nAChRsubtype are preferred. The compounds of the invention are indicated aspharmaceuticals, in particular in the treatment or prophylaxis ofpsychotic disorders and intellectual impairment disorders. Examples ofpsychotic disorders include schizophrenia, mania and manic depression,and anxiety. Examples of intellectual impairment disorders includeAlzheimer's disease, learning deficit, cognition deficit, attentiondeficit, memory loss, and Attention Deficit Hyperactivity Disorder. Thecompounds of the invention may also be useful as analgesics in thetreatment of pain (including chronic pain) and in the treatment orprophylaxis of Parkinson's disease, Huntington's disease, Tourette'ssyndrome, and neurodegenerative disorders in which there is loss ofcholinergic synapses. The compounds may further be indicated for thetreatment or prophylaxis of jetlag, for use in inducing the cessation ofsmoking, and for the treatment or prophylaxis of nicotine addiction(including that resulting from exposure to products containingnicotine).

It is also believed that compounds according to the invention are usefulin the treatment and prophylaxis of ulcerative colitis.

Pharmacology

The pharmacological activity of the compounds of the invention may bemeasured in the is tests set out below:

Test A—Assay for Affinity at α7 nAChR Subtype

₁₂₅I-αL-Bunparotoxin (BTX) binding to rat hippocampal membranes. Rathippocampi were homogenized in 20 volumes of cold homogenization buffer(BB: concentrations of constituents (mM):tris(hydroxymethyl)aminomethane 50; MgCl₂1; NaCl120; KCl 5: pH 7.4). Thehomogenate was centrifuged for 5 minutes at 1000 g, the supernatant wassaved and the pellet re-extracted. The pooled supernatants werecentrifuged for 20 minutes at 12000 g, washed, and resuspended in HB.Membranes (30-80 μg) were incubated with 5 nM [¹²⁵I]α-BTX, 1 mg/mL BSA(bovine serum albumin), test drug, and either 2 mM CaCl₂ or 0.5 mM EGTA[ethylene glycol-bis(β-aminoethylether)] for 2 hours at 21° C., and thenfiltered and washed 4 times over Whatman lass fibre filters (thicknessC) using a Brandel cell harvester. Pretreating the filters for 3 hourswith 1% (BSA/0.01% PEI (polyethyleneimine) in water was critical for lowfilter blanks (0.07% of total counts per minute). Nonspecific bindingwas described by 100 μM (−)-nicotine, and specific binding was typically75%.

Test B—Assay for Affinity to the α4 nAChR Subtype

[³H]-(−)-nicotine binding. Using a procedure modified fromMartino-Barrows and Kellar (Mol Pharm (1987) 31:169-174), rat brain(cortex and hippocampus) was homogenized as in the [₁₂₅I]α-BTX bindingassay, centrifuged for 20 minutes at 12,000×g, washed twice, and thenresuspended in HB containing 100 μM diisopropyl fluorophosphate. After20 minutes at 4° C., membranes (approximately 0.5 mg) were incubatedwith 3 nM [3H]-(−)-nicotine, test drug, 1 μM atropine, and either 2 mMCaCl₂ or 0.5 mM EGTA for 1 hour at 4° C., and then filtered over Whatmanglass fibre filters (thickness C) (pretreated for 1 hour with 0.5% PEI)using a Brandel cell harvester. Nonspecific binding was described by 100μM carbachol, and specific binding was typically 84%.

Binding Data Analysis for Tests A and B

IC₅₀ values and pseudo Hill coefficients (n_(H)) were calculated usingthe non-linear curve fitting program ALLFIT (DeLean A, Munson P J andRodbard D (1977) Am. J. Physiol., 235:E97-E102). Saturation curves werefitted to a one site model, using the nonlinear regression programENZFITTER (Leatherbarrow, R. J. (1987)), yielding K_(D) values of 1.67and 1.70 nM for the ¹²⁵I-α-BTX and [³H]-(−)-nicotine ligandsrespectively. K_(i) values were estimated using the generalCheng-Prusoff equation:

K _(i) −[IC ₅₀]/((2+([ligand]/[K _(D)])_(n))_(l/n)−1)

where a value of n=1 was used whenever n_(H)<1.5 and a value of n=2 wasused when n_(H)≧1. Samples were assayed in triplicate and were typically+5%. K_(i) values were determined using 6 or more drug concentrations.The compounds of the invention are compounds with binding affinities(K_(i)) of less than 1000 nM in either Test A or Test B, indicating thatthey are expected to have useful therapeutic activity.

The compounds of the invention have the advantage that they may be lesstoxic, be more efficacious, be longer acting, have a broader range ofactivity, be more potent, produce fewer side effects, are more easilyabsorbed or have other useful pharmacological properties.

EXAMPLES

Commercial reagents were used without further purification. Mass spectrawere recorded using either a Hewlett Packard 5988A or a MicroMassQuattro-1 Mass Spectrometer and are reported as m/z for the parentmolecular ion with its relative intensity. Room temperature refers to20-25° C.

Preparation 1

Spiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane]N-borane complex

A mixture of trimethylsulfoxonium iodide (16.10 g, 73.2, mmol) and adispersion of 4 sodium hydride (60% in oil, 3.00 g, 75.0 mmol) inanhydrous dimethyl sulfoxide was stirred at room temperature undernitrogen for 30 minutes. Quinuclidin-3-one (7.05 g, 56.3 mmol) was thenadded as a solid portionwise, and the resulting mixture was stirred at65-70° C. under nitrogen for 1 hour. The reaction mixture was cooled,water was added (200 mL), and the resulting solution was extracted withchloroform (3×200 mL). The chloroform extracts were combined, andback-extracted with water (4×200 mL). The chloroform layer was thendried (MgSO₄), filtered, and evaporated under reduced pressure to affordspiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane] (6.51 g,46.8 mmol, 83%) asa clear, colorless liquid. To a stirred solution ofspiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane] (5.3 g, 38.1 mmol) inanhydrous tetrahydrofuran (100 mL) at 0° C. was added dropwise asolution of borane in tetrahydrofuran (1.0 M, 38.1 mL, 38.1 =mmol), andresulting solution was stirred at 0° C. under nitrogen for 30 minutes.Brine (100 mL) was added cautiously to the reaction solution, and theresulting aqueous mixture was extracted with ethyl acetate (2×100 mL).The organic extracts were combined, dried (MgSO₄), filtered, andevaporated under reduced pressure to afford the title compound (4.3 g,28.1 mmol, 74%) as a white solid: electrospray MS 152 ([M−H]⁺, 15).

Preparation 2

3-(2-Chloropyridin-3-ylmethyl)-3-hydroxy-1-azabicyclo[2.2.2]octaneN-borane complex

A solution of phenyllithium (1.8 M in cyclohexane/ether [7:3], 167 mL,0.3 mol, 3 eq.) was added via a cannula to anhydrous tetrahydrofuran(350 mL) at −60° C. under a nitrogen atmosphere. Then, diisopropylamine(0.7 mL, 5 mmol) was added dropwise, followed by a dropwise addition of2-chloropyridine (28.4 mL, 0.3 mol, 3 eq.) over ten minutes. Theresulting solution was stirred at −40° C. under nitrogen for 1.5 hours.The solution was then cooled to −60° C., and a solution ofspiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane] N-borane complex (15.3 g,0.1 mol) in tetrahydrofuran (75 mL) was added dropwise. The resultingreaction mixture was then stirred at −40° C. under nitrogen. After 3hours, a saturated solution of sodium bicarbonate (150 mL) was slowlyadded, followed by water (400 mL), and the resulting aqueous mixture wasallowed to warm to room temperature. The layers were separated and theaqueous phase was extracted with ethyl acetate (3×100 mL). The organiclayers were combined, dried (MgSO₄), filtered, and evaporated underreduced pressure. Column chromatography using silica gel and elutionwith ethyl acetate/hexanes [3:2] afforded the title compound as a tansolid (17.5 g, 65.6 mmol, 66%): electrospray MS 269 ([MH]⁺ with ³⁷Cl,10), 267 ([MH]⁺ with ³⁵Cl, 26).

Preparation 2(b)

3-(2,4-Dichloropyridin-3-ylmethyl)-3-hydroxy-1-azabicyclo[2.2.2]octaneN-borane complex

was prepared from 2.64 g (17.8 mmol) of 2,4-dichloropyridine and 1.37 g(8.95 mmol) of spiro[1-azabicyclo[2.2.2]octane-3,2′oxirane], providing2.42 g (90%), m.p. 178-179° C. (1:1 ethyl acetate-hexane).

Preparation 3

Spiror[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furor[2.3-b]pyridine]N-borane complex

3-(2-Chloropyridin-3-ylmethyl)-3-hydroxy-1-azabicyclo[2.2.2]octaneN-borane complex (17.4 g, 65.3 mmol) was dissolved in anhydrousN,N-dimethylformamide (500 mL), the resulting solution was cooled to 0°C. under nitrogen, and a dispersion of sodium hydride (60% in oil, 6.55g, 163 mmol, 2.5 eq.) was added portionwise. The resulting solution wasstirred at room temperature under nitrogen for 16 hours. A saturatedsolution of ammonium chloride (50 mL) was then added at 0° C., followedby ice water (500 mL), and the resulting aqueous mixture was extractedwith chloroform (4×125 mL). The organic extracts were combined, dried(MgSO₄), and evaporated under reduced pressure to afford an orangesolid. Purification through a short column of silica gel eluting withchloroform/acetone [95:5 to 85:15], followed by stirring in hexanes (100mL) and filtration, provided a yellow solid (12.7 g, 55.2 mmol, 84%) ofthe title compound: electrospray MS 231 ([MH]⁺, 65).

Preparation 4

3-(2-Methanesulfonyloxyethyl)-3-trimethylsilyloxy-1-azabicyclo[2.2.2]octaneN-borane complex (a) 2-(3-Hydroxy-1-azabicyclo[2.2.2]oct-3-yl)aceticacid t-butyl ester

To a solution of diisopropylamine (6.7 mL) in tetrahydrofuran (THF) (20mL) at 0° C. was added n-butyllithium (2.3M in hexanes; 20 mL). Thereaction mixture was stirred for 40 minutes and then cooled to −78° C.To this mixture a solution of t-butyl acetate (6.4 mL) in THF (10 mL)was added dropwise and stirring was continued for an additional 15minutes. Quinuclidin-3-one (5 g) in THF (15 mL) was added to the mixturedropwise and the mixture was allowed to warm to 0° C. over 1 hour. Tothis solution water (100 mL) was added, the solution was extracted twicewith chloroform and the combined extracts were washed once with brine.The resulting solution was dried over MgSO₄, filtered, and evaporated invacuo to give 9.53 g of the subtitle compound as an off-white solid.

(b) 2-(3-Hydroxy-1-azabicyclo[2.2.2]oct-3-yl)acetic acid methyl ester

Trifluoroacetic acid (40 mL) was added dropwise over 15 minutes to asolution of 2-(3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl)acetic acid t-butylester (15.7 g) in anhydrous dichloromethane (40 mL) at 0° C. The mixturewas stirred for 24 hours at room temperature, then the solvent wasevaporated under reduced pressure. The residue was dissolved in methanol(90 mL) and cooled in an ice bath. Concentrated sulfuric acid (9 mL) wasadded dropwise over 10 minutes, then the reaction mixture was stirred atroom temperature. After 3 hours, the solution was poured into 100 mL ofice water, basified to pH 10 with saturated aqueous sodium carbonatesolution, and extracted with chloroform (4×100 mL). The extracts weredried (MgSO₄), filtered, and evaporated in vacuo to give a solid.Recrystallization from ethyl acetate provided 6.3 g of the tancrystalline subtitle compound.

(c) 2-(3-Hydroxy-1-azabicyclo[2.2.2]oct-3-yl)acetic acid methyl esterN-borane complex

Borane in THF (1M, 5.25 mL) was added dropwise over 20 minutes to asolution of 2-(3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl)acetic acid methylester (1 g) in anhydrous tetrahydrofuran (THF) (20 mL) stirred at 0° C.After 30 minutes, 20 mL of brine was added, stirring was continued for afurther 30 minutes and the layers were then separated. The aqueous layerwas extracted with ethyl acetate (2×20 mL), the organic layers werecombined, and then dried (MgSO₄), filtered, and evaporated under reducedpressure. The residue was subjected to flash chromatography on silicagel (eluting with chloroform/acetone, 95:5) to give the title compound(900 mg) as an off-white solid.

(d) 3-Hydroxy-3-(2-hydroxyethyl)-1-azabicyclo[2.2.2]octane N-boranecomplex

Under an argon atmosphere, lithium borohydride (2M in tetrahydrofuran,2.6 mL, 5.2 mmol) was added over 5 minutes to a solution of2-(3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl)acetic acid methyl esterN-borane complex (1 g, 4.7 mmol) in anhydrous tetrahydrofuran (20 mL)and heated at reflux for 1 hour. The reaction was cooled (ice bath),quenched with water (5 mL) and saturated aqueous sodium bicarbonate (5mL), stirred for 45 minutes at 0° C. to room temperature, and extractedfour times with ethyl acetate. The combined organic layers were dried(MgSO₄), evaporated under reduced pressure and triturated with ethylether to obtain the title compound (830 mg, 4.5 mmol, 95%) as a whitesolid.

(e)3-Trimethylsilyloxy-3-(2-trimethylsilyloxyethyl)-1-azabicyclo[2.2.2]octaneN-borane complex

Under an argon atmosphere, chlorotrimethylsilane (0.255 mL, 2 mmol) wasadded via syringe over 5 minutes to3-hydroxy-3-(2-hydroxyethyl)-1-azabicyclo[2.2.2]octane N-borane complex(185 mg, 1 mmol) in dry 1-methylimidazole (1 mL) at 0° C.N-(trimethylsilyl)acetamide (262 mg, 2 mmol) was added in one portion,the reaction was stirred for 16 hours at room temperature and heated at55-60° C. for 3 hours. The mixture was cooled, poured into ice/water (5g), and extracted four times with ether. The combined organic layerswere washed four times with brine, dried (MgSO₄), evaporated underreduced pressure and purified by flash chromatography (eluting withhexane/ethyl acetate, 3:2) to obtain the title compound (210 mg, 0.64mmol, 64%).

(f) 3-(2-Hydroxyethyl)-3-trimethylsilyloxy-1-azabicyclo[2.2.2]octaneN-borane complex

Under an argon atmosphere,3-trimethylsilyloxy-3-(2-trimethylsilyloxyethyl)-1-azabicyclo[2.2.2]octaneN-borane complex (190 mg, 0.58 mmol) in anhydrous methanol (1 mL)containing 0.032 M potassium carbonate in methanol (0.25 mL) was stirredat room temperature for 84 hours, acidified to pH 7 with acetic acid,and evaporated under reduced pressure. Purification by flashchromatography (eluting with hexane/ethyl acetate, 3:2) provided thetitle compound (94 mg, 0.37 mmol, 63%).

(g)3-(2-Methanesulfonyloxyethyl)-3-trimethylsilyloxy-1-azabicyclo[2.2.2]octaneN-borane complex

Under an argon atmosphere, methanesulfonyl chloride (0.086 mL, 1.1 mmol)in anhydrous pyridine (1 mL) was added over 20 minutes at 0° C.-5° C. toa solution of3-(2-hydroxy-ethyl)-3-trimethylsilyloxy-1-azabicyclo[2.2.2]octaneN-borane complex (257 mg, 1 mmol) in anhydrous pyridine (4 mL), stirredat 0° C. for 20 minutes, and at room temperature for 2 hours. Pouredinto ice (15 g), extracted four times with ethyl acetate, combined theorganic layers, and washed sequentially with 1 N aqueous hydrochloricacid (three times), water, and saturated aqueous sodium bicarbonate. Theextracts were dried (MgSO₄), evaporated under reduced pressure andpurified by flash chromatography (eluting with chloroform/ethyl acetate,97:3) to obtain the title compound (263 mg, 0.78 mmol, 78%).

Preparation 5

(a) 3-Ethenyl-3-hydroxy-1-azabicyclo[2.2.2]octane

Under an argon atmosphere, a solution of 3-quinuclidinone (1.25 g, 10mmol) in anhydrous tetrahydrofuran (10 mL) was added over 15 minutes toa 1 M solution of vinylmagnesium bromide in tetrahydrofuran (20 mL, 20mmol) at 0° C. to 5° C., stirred at room temperature for 24 hours,cooled to 0° C., and acidified to pH 1 with 6 M hydrochloric acid. Themixture was stirred for 15 minutes, basified to pH 10 with 25% aqueoussodium hydroxide, extracted with chloroform (4×50 mL) andchloroform/methanol (4:1, 50 mL), combined the organic layers, dried(MgSO₄), evaporated under reduced pressure and purified by flashchromatography (eluting with ammoniated chloroform/methanol, 85:15) toobtain the title compound (830 mg, 5.4 mmol, 54%).

(b) 3-Bromo-2-hydroxypyridine

A solution of bromine (9.6 g, 60 mmol) in 1 M aqueous potassium bromide(120 mL) was added over 5 minutes to a solution of 2-hydroxypyridine(5.7 g, 60 mmol in 1 M aqueous potassium bromide (60 mL) and stirred for24 hours. The solid precipitate was filtered off the aqueous phase wassaturated with sodium chloride and extracted with chloroform (4×20 mL),the combined extracts were dried (MgSO₄), evaporated under reducedpressure and combined with the original precipitate. Purification byflash chromatography (eluting with ammoniated chloroform/methanol, 95:5)and recrystallization from acetonitrile provided the title compound(3.62 g, 20.8 mmol, 35%).

(c) 3-Bromo-2-methoxypyridine

Under an argon atmosphere, a mixture of 3-bromo-2-hydroxypyridine (3.49gd 20 mmol), silver carbonate (3.67 g, 13.31 mmol), and iodomethane (1.5mL, 24.1 mmol) in benzene (30 mL) was stirred in the dark at 40° C. to50° C. for 24 hours, cooled in an ice bath, and filtered. The filtratewas washed once with 2% aqueous sodium bicarbonate and twice with water,dried (MgSO₄), the benzene was evaporated at atmospheric pressure, andthe residue was purified by flash chromatography (eluting withhexane/ethyl acetate, 2:1) to obtain the title compound (2.35 g, 12.5mmol, 62%).

Example 1 Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

5′-Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]N-borane complex (12.2 g, 53 mmol) was dissolved in 150 mL of acetone,the solution was cooled to 0° C., and an aqueous solution of HBr (24%;50 mL) was added. The resulting solution was stirred at room temperatureunder nitrogen for 24 hours. The reaction was concentrated under reducedpressure, and the aqueous residue was treated with saturated aqueoussodium carbonate solution (50 mL). The solution was basified to pH >10using solid sodium carbonate, and the resulting solution was extractedwith chloroform (3×100 mL). The organic extracts were combined, dried(MgSO₄), filtered, and evaporated under reduced pressure to afford thetitle compound (11.2 g, 51.8 mmol, 98%, 54% overall) as an off-whitesolid: electrospray MS 217 ([MH]⁺, 72).

The title compound was separated into its (R)- and (S)-enantiomers byeither of the following methods:

Method A—250 mg of the title compound was separated by chiral HPLC,using a 2 cm×25 cm CHIRALCEL-OD column on a Waters Delta Prep 3000Preparative Chromatography System, eluting with2,2,4-trimethylpentane/ethanol (92:8 to 9:1) at a flow rate of 20mL/min. This provided 111 mg of the (S)-enantiomer ([α]²³=+59.7° (c=1,methanol)) and 90 mg of the (R)-enantiomer ([α]²³=−63.9° (c=1,methanol)).

Method B—1 g (4.62 mmol) of the title compound was treated withL-(+)-tartaric acid (694 mg; 4.62 mmol) in 15% aqueous ethanol (10 mL)and recrystallized three times to obtain the (S)-enantiomerL-(+)-tartrate (650 mg; 1.77 mmol; [α]²³=+57.7° (c=2, H₂O)). Thefiltrates were concentrated under reduced pressure and the aqueousresidue was basified to pH>10 using solid sodium carbonate. Theresulting mixture was extracted with chloroform (3×25 mL) and thecombined extracts were dried (MgSO₄), and evaporated under reducedpressure. The residue (650 mg; 3 mmol) was treated with D-(−)-tartaricacid (452 mg; 3 mmol) and recrystallized as above to provide the(R)-enantiomer D-(−)-tartrate (775 mg; 2.11 mmol; [α]²³=−58.2° (c=2,H₂O)).

Example 2A5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

A solution ofspiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (100 mg,0.462 mmol) and sodium acetate (410 mg, 5 mmol) in 50% aqueous aceticacid (4 mL) was heated to 60° C. Bromine (0.100 mL, 1.94 mmol) was addedvia a syringe over 10 minutes, and the solution was then heated underreflux for 1 hour. The mixture was allowed to cool to ambienttemperature, basified to pH >10 with sodium carbonate, and extractedwith chloroform (3×15 mL). The combined extracts were dried (MgSO₄),filtered, and evaporated under reduced pressure to give the titlecompound (110 mg, 0.37 mmol, 81%) as an off-white solid: electrospray MS295 ([MH]⁺, with ⁷⁹Br, 100), 297 ([MH]⁺, with ⁸¹Br, 98).

Example 2B(R)-(−)-5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

The enantiomer(R)-(−)-spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](1.95 g, 9 mmol) treated in the same way as described in example 2Aprovided the title compound (1.77 g, 6 mmol, 67%) ([α]²³=−45.5° (c=1,MeOH)).

Example 35′-Phenylspiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Under a nitrogen atmosphere,5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](118 mg, 0.4 mmol), phenylboronic acid (54 mg, 0.443 mmol), andtetrakis(triphenylphosphine)palladium(0) (11 mg, 2.3 mol %) were stirredin a solution of 1,2-dimethoxyethane (3 mL) and ethanol (0.75 mL)containing 2M aqueous sodium carbonate (0.65 mL, 1.3 mmol). The mixturewas heated under reflux for 18 hours. The reaction mixture was thenevaporated under reduced pressure, the residue was dissolved inchloroform (15 mL), and the extract was washed with saturated aqueoussodium carbonate (5 mL). The aqueous layer was extracted with chloroform(2×15 mL), and the organic layers were combined, dried (MgSO₄),filtered, and evaporated under reduced pressure. Purification by flashchromatography through silica gel, eluting with ammoniatedchloroform/methanol (95:5 to 9:1), provided the title compound (80 mg,0.274 mmol, 68%) as a tan solid: electrospray MS 293 ([MH]⁺, 100).

Example 4A5′-Nitrospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

A mixture ofspiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (325 mg,1.5 mmol) and fuming nitric acid (0.27 mL, 5.74 mmol) in sulfuric acid(0.75 mL) was heated at 70° C. to 80° C. for 24 hours. The resultingviscous solution was poured onto 15 g of ice and basified to pH >10 withsolid sodium carbonate. The resulting mixture was extracted withchloroform (4×15 mL), dried (MgSO₄), filtered, and evaporated underreduced pressure. Purification by flash chromatography through silicagel, eluting with ammoniated chloroform/methanol (95:5), provided thetitle compound (200 mg, 0.765 mmol, 51%) as a light yellow solid:electrospray MS 262 ([MH]⁺, 100).

Example 4B(R)-(−)-5′-Nitrospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(R)-(−)-Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](3.03 g, 14 mmol) was dissolved in concentrated sulfuric acid (7 mL) at0-5° C., fuming nitric acid (3.3 mL, 70.2 mmol) was added over 10minutes, the mixture was stirred for 1 hour, and heated at 65-70° C. for24 hours. Cooled, poured onto ice (200 gm), added 300 mL of water,basified to pH 10 with solid potassium carbonate, stirred for 1 hour,filtered off and dried the solid title compound (3.6 g, 13.8 mmol, 98%):electrospray MS (m/z, relative intensity) 262 ([MH]⁺, 100).

Example 4C(S)-(+)-5′-Nitrospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

The enantiomer(S)-(+)-spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](6.5 g, 30 mmol) treated in the same way as described in example 4Bprovided the title compound (7.75 g, 29.7 mmol, 99%): electrospray MS(m/z, relative intensity) 262 ([MH]⁺, 100).

Example 5Spiro[1-Azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]quinoline]

The title compound was prepared by a procedure analogous to thatdescribed in Example 1 om 2-chloroquinoline (0.99 g, 6.06 mmol) andspiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane] N-borane complex (0.31 g,2.0 mmol), yielding the title compound (0.135 g) as a beige powder,electrospray MS 267 [MH]⁺.

The two enantiomers were resolved on a Chiral OD column by elution withan 8-10% EtOH/hexane gradient, and UV detection. First enantiomer: 100%chiral purity by LC, Rt=12.32 minutes, [α]_(D) at 23° in EtOH=+47.9°.Second enantiomer: 99.4% chiral purity, Rt=17.84 minutes, [α]_(D)=−48.5.

Example 61′-Chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]isoguinoline]

The title compound was prepared by a procedure analogous to thatdescribed in Example 1 from 1,3-dichloroisoquinoline (2.41 g, 12.2nmnol) and spiro[I-azabicyclo[2.2.2]octane-3,2′-oxirane] N-boranecomplex (0.62 g, 4.05 mmol), yielding 0.86 g of1′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]isoquinoline]N-borane complex, electrospray MS 314 [MH⁺]. Removal of the borane groupfrom 65 mg of the N-borane complex gave 30 mg of the title compound,electrospray MS 301 [MH⁺].

Example 7Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]isoquinoline]

The borane protected chloride of Example 6 (0.3; or 0.96 mmol) wassuspended in a mixture of glacial acetic acid (6.0 ml) and water (0.5ml). The suspension was placed under nitrogen and zinc dust (150 mg) wasadded. The reaction mixture was stirred at 70° C. for 5 hours. Thereaction mixture was allowed to cool and was then poured into saturatedNaHCO₃. Enough aqueous NaHCO₃ was added to give a basic pH, and theproducts were extracted with three portions of chloroform. The combinedchloroform extract was dried (MgSO₄), filtered, and evaporated in vacuo.Two runs were combined for purification on a silica flash column, usinga gradient from 2:1 hexane/ethyl acetate to 100% ethyl acetate. Thefaster eluting compound wasspiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]isoquinoline]N-borane complex and the slower eluting compound was the title compound.Yield 100%: chemical ionization MS 279 [MH]⁺−H₂ for the N-borane complexand 267 [MH]⁺for the title compound. Removal of the borane group underthe conditions of Example 1 followed by flash chromatography gave thetitle compound as a brown semi-solid: chemical ionization MS 267 [MH]⁺.

Example 8A5′-Aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

A mixture of5′-nitrospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](1.4 g 5.36 mmol), and 10% palladium on carbon (48% water wet, 270 mg)in methanol (90 mL) was hydrogenated for 1 hour at 50 psi of hydrogen.The catalyst was filtered off through a pad of celite and the solventwas evaporated under reduced to obtain the amine (1.2 g, 5.25 mmol, 98%)as a tan solid: electrospray MS (m/z, relative intensity) 232 ([MH]⁺,100).

The title compound was separated into its (R)- and (S)- enantiomers bythe following method:

150 mg of the title compound was separated by chiral HPLC, using a 2cm×25 cm CHIRALCEL-OD column on a Waters Delta Prep 4000 PreparativeChromatography System [hexane/ethanol (85:15 to 8:2)] at a flow rate of20 mL/min. This provided 52 mg of the (S)-epimer ([α]²²=+62° (c=1,ethanol) and 52 mg of the (R)-epimer ([α]²³=−64° (c=1, ethanol).

Example 8B(R)-(−)-5′-Aminospiro[1-azabicyclo-[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

The enantiomer(R)-(−)-5′-nitrospiro[1-azabicyclo-[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](3.8 g, 13.3 mmol) treated in the same way as described in example 8A,and purified by flash chromatography (eluting with ammoniatedchloroform/methanol, 95:5 to 85:15), provided the title compound (2.5 g,10.8 mmol, 81%): electrospray MS (m/z, relative intensity) 232 ([MH]⁺,100).

Example 8C(S)-(+)-5′-Aminospiro[1-azabicyclo-[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

The enantiomer(S)-(+)-5′nitrospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](6.85 g, 26.2 mmol) treated in the same way as described in example 8Ain ammoniated methanol provided the title compound (5.55 g, 24 mmol,92%): electrospray MS (m/z, relative intensity) 232 ([MH]⁺, 100).

Example 9 5′-Phenylcarboxamidospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Under a nitrogen atmosphere, benzoic acid (67 mg, 0.55 mmol),O-(1H-benzotriazol-1-yl)-N,N,N′N′-tetramethyluronium tetrafluoroborate(“TBTU”, 176 mg, 0.55 mmol), 1-hydroxybenzotriazole hydrate (“HOBT”, 78mg, 0.55 mmol), and diisopropylethylamine (0.193 mL, 1.1 mmol) werecombined in anhydrous N,N-dimethylformamide (8 mL) and stirred for 10minutes.5′-Aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](115 mg, 0.5 mmol) was added as a solid in one portion and stirring wascontinued for 3 days. The solvent was evaporated under high vacuum to55° C. and the residue was partitioned between saturated aqueous sodiumcarbonate (2 mL) and dichloromethane (10 mL). After separating, theaqueous layer was extracted with dichloromethane (2×5 mL). The organiclayers were combined, dried (MgSO₄), and evaporated under reducedpressure. Purification by flash chromatography through silica gel,eluting with ammoniated chloroform/methanol (9:1), provided the titlecompound (125 mg, 0.372 mmol, 75%) as a yellow solid: electrospray MS(m/z, relative intensity) 336 ([MH]⁺, 100).

Example 105′-Phenylaminocarbonylaminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Under a nitrogen atmosphere, phenyl isocyanate (0.056 mL, 0.515 mmol)was added to a suspension of5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](119 mg, 0.514 mmol) in anhydrous tetrahydrofuran (5 mL) and stirred for12 hours. The solvent was evaporated under reduced pressure and theresidue purified by flash chromatography through silica gel, elutingwith ammoniated chloroform/methanol (92.5:7.5), to obtain the titlecompound (155 mg, 0.442 mmol, 86%) as an off-white solid: electrosprayMS (m/z, relative intensity) 351 ([MH]⁺, 100).

Example 115′-Phenylsulfonylamidospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Under a nitrogen atmosphere, benzenesulfonyl chloride (0.07 mL, 0.55mmol) was added to a solution of5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](115 mg, 0.5 mmol) in anhydrous pyridine (5 mL) and stirred for 4 hours.The solvent was evaporated under high vacuum, the residue waspartitioned between saturated aqueous sodium carbonate (2 mL) andchloroform (10 mL), separated and extracted the aqueous phase withchloroform (2×5 mL). The combined organic layers were dried (MgSO₄), thesolvent was evaporated under reduced pressure, and the residue wasre-evaporated from ethanol (3×10 mL) under reduced pressure. Thisafforded the title compound (179 mg, 0.5 mmol, 100%) as a yellow solid:electrospray MS (m/z, relative intensity) 372 ([MH]⁺, 100).

Example 125′-(N-Methylamino)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Under a nitrogen atmosphere, sodium (50 mg, 2.17 mmol) was slowly added(exothermic) to methanol (1 mL) and stirred for 1 hour.5′-Aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](115 mg, 0.5 mmol) and paraformaldehyde (35 mg, 1.17 mmol) were addedand stirred for 16 hours. The reaction was heated at 50° C. for 4 hours,sodium borohydride (53 mg, 1.4 mmol) was added, and heated at reflux for1 hour. Then, 1 N aqueous potassium hydroxide (0.4 mL) was added andcontinued at reflux for 2 hours more. The solvent was evaporated underreduced pressure, the residue was partitioned between water (1 mL) andchloroform (4 mL), separated and extracted the aqueous phase withchloroform (2×4 mL). The combined organic layers were washed with brine(1 mL), dried (MgSO₄), evaporated under reduced pressure, and purifiedby flash chromatography through silica gel (eluting with ammoniatedchloroform/methanol, 95:5) to obtain the title compound (78 mg, 0.32mmol, 64%) as an off-white solid: electrospray MS (m/z, relativeintensity) 246 ([MH]⁺, 100).

Example 13A5′-(N,N-Dimethylamino)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Sodium cyanoborohydride (63 mg, 1 mmol) was dissolved in methanol (2.5mL), anhydrous zinc chloride (69 mg, 0.5 mmol) was added, stirred for 30minutes, added the resulting solution to a solution of5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](115 mg, 0.5 mmol) and 37% aqueous formaldehyde (0.12 mL, 1.6 mmol) inmethanol (2.5 mL), and stirred for 20 hours. Poured into 1 N aqueouspotassium hydroxide (10 mL), stirred for 1 hour, evaporated underreduced pressure, and extracted the aqueous residue with chloroform(4×10 mL). The combined extracts were dried (MgSO₄), evaporated underreduced pressure, and purified by flash chromatography through silicagel (eluting with ammoniated chloroform/methanol, 97.5:2.5), to obtainthe title compound (85 mg, 0.33 mmol, 66%) as an off-white solid:electrospray MS (m/z, relative intensity) 260 ([MH]⁺, 100).

Example 13B(R)-(−)-5′-(N,N-Dimethylamino)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

The enantiomer(R)-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](231 mg, 1 mmol) treated in the same way as described in example 13Aprovided the title compound (178 mg, 0.69 mmol, 69%): electrospray MS(m/z, relative intensity) 260 ([MH]⁺, 100).

Example 14A(S)-(+)-5′-(E)-(Phenylethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

A solution of(S)-(+)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](150 mg, 0.51 mmol), styrene (0.07 mL, 0.61 mmol), palladium(II)acetate(1.2 mg, 0.0053 mmol), tri-o-tolylphosphine (6.4 mg, 0.021 mmol), andtriethylamine (0.5 mL, 3.6 mmol) in anhydrous acetonitrile (0.5 mL), ina heavy-walled threaded glass tube containing a magnetic stir bar, waspurged with argon and sealed with a Teflon plug and FETFE O-ring. Themixture was stirred and heated at 100° C. for 2 hours, cooled to roomtemperature, dissolved in chloroform (10 mL), washed with saturatedaqueous sodium carbonate (1 mL), dried (MgSO₄), and evaporated underreduced pressure. Recrystallization from ethyl acetate afforded thetitle compound (90 mg, 0.28 mmol, 55%) as a light tan solid:electrospray MS (m/z, relative intensity) 319 ([MH]⁺, 100).

Example 14B(R)-(−)-5′-(E)-(Phenylethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Treatment of the enantiomer(R)-(−)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](295 mg, 1 mmol) in the same way as described in example 14A, andpurification by flash chromatography (eluting with ammoniatedchloroform/methanol, 98:2 to 96:4) provided the title compound (132 mg,0.41 mmol, 41%): electrospray MS (m/z, relative intensity) 319 ([MH]⁺,100).

Example 15A(S)-(+)-5′-(4-Morpholino)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Sodium tert-butoxide (56.6 mg, 0.59 mmol),tris(dibenzylideneacetone)dipalladium (15.4 mg, 0.017 mmol), and2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (21 mg, 0.034 mmol) werecombined in a heavy-walled threaded glass tube containing a magneticstir bar, and purged with argon. Added(S)-(+)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](130 mg, 0.44 mmol), morpholine (0.066 mL, 0.76 mmol) and anhydroustetrahydrofuran (3 mL), sealed with a Teflon plug and FETFE O-ring,stirred and heated at 100° C. for 72 hours. The mixture was cooled toroom temperature, dissolved in chloroform (25 mL), washed-with brine(3×2 mL), dried (MgSO4), evaporated under reduced pressure, purified byflash chromatography through silica gel (eluting with ammoniatedether/methanol, 4:1), and recrystallized from ethyl acetate to obtainthe title compound (35 mg, 0.12 mmol, 26%) as a tan solid: electrosprayMS (m/z, relative intensity) 302 ([MH]⁺, 100).

Example 15B(R)-(−)-5′-(4-Morpholino)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Treatment of the enantiomer(R)-(−)-5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](580 mg, 1.965 mmol) in the same way as described in example 15A,provided the title compound (187 mg, 0.62 mmol, 32%): electrospray MS(m/z, relative intensity) 302 ([MH]⁺, 100).

Example 16(R)-(−)-5′-(1-Azetidinyl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(R)-(−)-5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](295mg, 1 mmol), azetidine (0.101 mL, 1.5 mmol), sodium tert-butoxide (135mg, 1.4 mmol), tris(dibenzylideneacetone)dipalladium (46 mg, 0.05 mmol),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (62 mg, 0.1 mmol) andanhydrous tetrahydrofuran (9 mL) were combined in a heavy-walledthreaded glass tube containing a magnetic stir bar, purged with argon,and sealed with a Teflon plug and FETFE O-ring. The mixture was stirredand heated at 75° C. for 4 hours, cooled to room temperature, dissolvedin chloroform (20 mL), washed with brine (3×10 mL), dried (MgSO₄),evaporated under reduced pressure, and purified by flash chromatographythrough silica gel (eluting with amnmoniated chloroform/methanol 95:5)to procure the title compound (230 mg, 0.0.85 mmol, 85%) as a light tansolid: chemical ionization MS (m/z, relative intensity) 272 ([MH]⁺, 56).

Example 17(R)-(−)-5′-(2-(4-Pyridyl)ethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(R)-(−)-5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](295 mg 1 mmol), 4-vinylpyridine (0.135 mL, 1.25 mmol),palladium(II)acetate (7.2 mg, 0.032 mmol), tri-o-tolylphosphine (38.7mg, 0.127 mmol), and triethylamine (0.5 mL, 3.6 mmol) in anhydrousacetonitrile (0.5 mL) were combined in a heavy-walled threaded glasstube containing a magnetic stir bar, purged with argon and sealed with aTeflon plug and FETFE O-ring. The mixture was stirred and heated at 100to 105° C. for 48 hours, cooled to room temperature, dissolved inchloroform (25 mL), washed with saturated aqueous sodium carbonate (2mL), dried (MgSO₄), and evaporated under reduced pressure. Purificationby flash chromatography through silica gel (eluting with ammoniatedchloroform/methanol, 95:5), followed by recrystallization from acetoneafforded the title compound (230 mg, 0.72 mmol, 72%): electrospray MS(m/z, relative intensity) 320 ([MH]⁺, 100).

Example 18(R)-(−)-5′-(2-(2-Pyridyl)ethenyl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(R)-(−)-5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](150mg, 0.5 mmol) was treated with 2-vinylpyridine (0.070 mL, 0.65 mmol) inthe same way as described in example 16. Purification by flashchromatography through silica gel (eluting with ammoniatedether/methanol, 95:5 to 9:1), followed by recrystallization fromacetonitrile produced the title compound (37 mg, 0.12 mmol, 23%):electrospray MS (m/z, relative intensity) 320 ([MH]⁺, 100).

Example 19(R)-(−)-5′-(2-Trimethylsilylethynyl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(R)-(−)-5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](295 mg, 1 mmol), trimethylsilylacetylene (0.355 mL, 2.5 mmol),tetrakis(triphenylphosphine)palladium (230 mg, 0.2 mmol), triethylamine(2 mL) and anhydrous acetonitrile (2 mL) were combined in a heavy-walledthreaded glass tube containing a magnetic stir bar, purged with argonand sealed with a Teflon plug and FETFE O-ring. The mixture was stirredand heated at 100° C. for 4 hours, cooled to room temperature, dissolvedin chloroform (25 mL), washed with saturated aqueous sodium carbonate (2mL), dried (MgSO₄), and evaporated under reduced pressure. Purificationby flash chromatography through silica gel (eluting with ammoniatedether/methanol, 9:1) afforded the title compound (280 mg, 0.90 mmol,90%): chemical ionization MS (mn/z, relative intensity) 313 ([MH]⁺, 30).

Example 20(R)-(−)-5′-Ethynylspiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Under an argon atmosphere, a 1 M solution of tetrabutylammonium fluoridein tetrahydrofuran (1.3 mL, 1.3 mmol) was added at 0° C. to a solutionof(R)-(−)-5′-(2-trimethylsilylethynyl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](265 mg, 0.85 mmol) in anhydrous tetrahydrofuran (5 mL), and stirred atroom temperature for 2 hours. The reaction was quenched with saturatedaqueous ammonium chloride solution (2 mL), extracted with ether (5×15mL), dried (MgSO₄), evaporated under reduced pressure, and purified byflash chromatography through silica gel (eluting with ammoniatedchloroform/methanol, 95:5) to obtain the title compound (121 mg, 0.50mmol, 59%): chemical ionization MS (m/z, relative intensity) 241 ([MH]⁺,19).

Example 215′-(2-Furyl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

A solution containing5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](103.5 mg, 0.351 mmol), tris(dibenzylidineacetone)dipalladium (0) (14mg, 0.015 mmol), tri(o-tolyl)phosphine (44.4 mg, 0.146 mmol), lithiumchloride (62 mg, 1.46 mmol), and 2-(tri-n-butylstannyl)furan (0.17 g,0.476 mmol) in 1,2-dimethoxyethane (1 ml) was heated under reflux for 2h. The solution was evaporated, and the residue was taken up inchloroform and filtered. The filtrate was evaporated then purified byHPLC using a gradient of 0-25% 1:1:2 7M methanolicammonia:methanol:chloroform and chloroform to obtain the title compound(89 mg, 0.313 mmol, 89%) as a pale solid: electrospray MS (m/z, relativeintensity) 283 ([MH]⁺, 100).

Example 225′-(3-Pyridyl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

A solution containing5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](158 mg, 0.535 mmol), tris(dibenzylidineacetone)dipalladium (0) (23 mg,0.025 mmol), tri(o-tolyl)phosphine (66 mg, 0.217 mmol), lithium chloride(99 mg, 2.34 mmol), and 3-(tri-n-butylstannyl)pyridine (0.3 ml, approx.0.3 g, approx. 0.82 mmol) in 1,2-dimethoxyethane (2 ml) was heated underreflux for 6 h. The solution was evaporated, and the residue was takenup in chloroform and filtered. The filtrate was evaporated then purifiedby HPLC using a gradient of 0-20% 1:1:2 7M methanolicammonia:methanol:chloroform and chloroform to obtain the title compound(58 mg, 0.198 mmol, 37%) as a pale solid: electrospray MS (m/z, relativeintensity) 294 ([MH]⁺, 80), 273 (100).

Example 235′-Methylspiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

A solution containing5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](203 mg, 0.687 mmol), tris(dibenzylidineacetone)dipalladium (0) (33 mg,0.036 mmol), tri(o-tolyl)phosphine (95 mg, 0.312 mmol), lithium chloride(241 mg, 5.69 mmol), and tetramethylstannane (1.0 ml, 1.3 g, 7.2 mmol)in 2-methoxyethyl ether (5 ml) was heated in a bath maintained at 100°C. After 3 h, a further portion of tetramethylstannane (1 ml, 1.3 g, 7.2mmol) was added, and heating was continued overnight. The solution wasfiltered, and subjected to purification by HPLC using a gradient of0-20% 1:1:2 7M methanolic ammonia:methanol:chloroform and chloroform toobtain the title compound (120 mg, 0.519 mmol, 76%) as a pale solid:electrospray MS (m/z, relative intensity) 231 ([MH]⁺, 100).

Example 24Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine-5′-carbonitrile]andSpiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine-5′-carboxamide]

A solution containing5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](165 mg, 0.558 mmol), and copper (I) cyanide (600 mg, 1.3 g, approx. 7.2mmol) in 1-methyl-2-pyrrolidinone (5 ml) was heated in a bath maintainedat 180° C. overnight and was then allowed to cool. The solution was thenpartitioned between aqueous ammonia and chloroform, and the organiclayer was separated, then dried (magnesium sulfate), filtered, andevaporated. The residue was subjected to purification by HPLC using agradient of 0-20% 1:1:2 7M methanolic ammonia:methanol:chloroform andchloroform to givespiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine-5′-carbonitrile](52 mg, 0.216 mmol, 39%) as a pale solid: DCI MS (m/z, relativeintensity) 242 ([MH]⁺, 100), andspiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine-5′-carboxamide](71 mg, 0.274 mmol, 49%) as a pale solid: electrospray MS (m/z, relativeintensity) 260 ([MH]⁺, 100).

Example 255′-Ethenylspiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

A solution containing5′-bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](150 mg, 0.508 mmol), tris(dibenzylidineacetone)dipalladium (0) (22 mg,0.024 mmol), tri(o-tolyl)phosphine (63 mg, 0.206 mmol), lithium chloride(103 mg, 2.43 mmol), and tri-n-butylvinylstannane (188 mg, 0.592 mmol)in 1,2-dimethoxyethane (10 ml) was heated under reflux overnight. Thesolution was evaporated, and the residue was taken up in chloroform andfiltered. The filtrate was evaporated then purified by HPLC using agradient of 0-25% 1:1:2 7M methanolic ammonia:methanol:chloroform andchloroform to obtain the title compound (93 mg, 0.385 mmol, 76%) as apale solid: electrospray MS (m/z, relative intensity) 243 ([MH]⁺, 100).

Example 26(R)-(−)-5′-N′-(3-Chlorophenyl)aminocarbonylaminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

The(R)-(−)-5′-Aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](65 mg or 0.28 mmoles) was suspended in 2.7 ml of anhydroustetrahydrofuran under nitrogen atmosphere. The 3-chlorophenylisocyanate(35 μl) was added and the suspension was stirred at ambient temperaturefor 5 hours. The tetrahydrofuran was removed in vacuo and the crude waspurified by flash chromatography. Elution with 20-40%methanol/chloroform (ammoniated with NH₄OH) gave the desired productspot product. The solvents were removed in vacuo and the residue wastaken up in chloroform and dried (MgSO₄). Evaporating, chasing with twoportions of ether, left 100 mg (92%) of white solid. Electrospray MS 385and 387 [MH]⁺.

Example 27(R)-(−)-5′-N′-(2-Nitrophenyl)aminocarbonylaminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Using the same method as in example 27 but substituting 2-nitrophenylisocyanate for 3-chlorophenylisocyanate the title compound was prepared;yield 97 mg (88%) of yellow powder. Electrospray MS 396 [MH]⁺.

Example 28(R)-(−)-5′-N,N-Diethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Sodium cyanoborohydride (190 mg or 3.0 mmoles) and the zinc chloride(206 mg or 1.5 mmoles) were added to 3.0 mls of anhydrous methanol undernitrogen atmosphere. Stirring for 5 minutes gave complete dissolution.The(R)-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](230 mg or 1.0 mmol) was added followed by acetaldehyde (0.335 mls or6.0 mmoles.) The suspension was stirred at ambient temperature for 16hours. The methanol was concentrated in vacuo and the suspension waspoured into 20 mls of 1 N sodium hydroxide. The aqueous layer wasextracted with four 20 ml portions of chloroform, and these werecombined dried (MgSO₄) and evaporated in vacuo. The crude was purifiedby flash chromatography, starting with 6/3/1/0.1 ethylacetate/methanol/water (ammoniated with NH₄₀OH) and then to 3/6/1/0.1.The solvents were removed in vacuo and the residue was taken up inchloroform and dried (MgSO₄.) Obtained 0.227 g (79%) of light brownsyrup. Electrospray MS 288 [MH]⁺.

Example 29(R)-(−)-5′-N-Ethylaminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(R)-(−)-5′-Aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](230 mg or 1.0 mmoles) and sodium cyanoborohydride were suspended in 6.2mls of anhydrous methanol. The acetaldehyde (90 μl or 1.1 mmoles) andthe solution was stirred at ambient temperature for 16 hours. Themethanol was removed in vacuo and the residue was taken up in 2 mls ofwater and 8 mls of chloroform. The layers were separated and the aqueouslayer was extracted 3 times more. The combined organic layers were dried(MgSO₄) and evaporated in vacuo. The crude product was purified by flashchromatography using a 3-15% methanol/chloroform (ammoniated) gradient.The solvents were evaporated in vacuo and chased with two portions ofether. The residue was suspended in ether and collected by filtration.After washing with ether and drying with high vacuum obtained 81 mg(31%) of white powder. Electrospray MS 260 [MH]⁺.

Example 30(R)-(−)-5′-N-Benzylaminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Prepared by the method of example 12. From 1.0 mmoles obtained 247 mg(77%) of white powder. Electrospray MS 322 [MH]⁺.

Example 31(R)-(−)-5′-N-Formamidospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

98% Formic acid (2.1 mls) and acetic anhydride (0.7 mls) were combinedunder nitrogen atmosphere and cooled with an ice bath. The(R)-(−)-5′-aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](230 mg or 1.0 mmoles) was added and the reaction was allowed to warm toambient temperature. The reaction was stirred for 26 hours and then waspoured with stirring into saturated sodium carbonate. Solid Na₂CO₃ wasadded until the pH was basic again, and then the aqueous layer wasextracted with four portions of chloroform. These were combined, dried(MgSO₄) and evaporated in vacuo. The crude was purified by flashchromatography eluting with a 2-10% ammoniated methanol/chloroformgradient. The solvents were removed in vacuo and the residue was takenup in chloroform, dried (MgSO₄) and evaporated in vacuo. The solvent waschased with two portions of ether giving 0.2 g (77%) of white solid.Electrospray MS 260 [MH]⁺.

Example 32(R)-(−)-5′-N-Acetamidospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

(R)-(−)-5′-Aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](230mg or 1.0 mmoles) was dissolved in 3 mls anhydrous pyridine undernitrogen atmosphere. The acetic anhydride (0.1 mls or 1.1 mmoles) wasadded and the solution was heated at 100° C. for 40 hours. The pyridinewas removed in vacuo, and the residue was taken up in 8 mls chloroformand washed with 4 mls of saturated sodium bicarbonate. The aqueous layerwas extracted twice more with chloroform and the combined organic layerswere dried (MgSO₄) and evaporated in vacuo. Purification by flashchromatography using a 3-20% ammoniated methanol/chloroform gradientgave the desired product. The solvents were removed in vacuo and chasedwith two portions of ether. Obtained 154 mg (56%) of white solid.Chemical ionization MS 274 [MH]⁺.

Example 334′-Chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]and4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[3,2-c]pyridine]

4′-Chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]borane complex and2′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[3,2-c]pyridine]borane complex were prepared from 2.36 g (7.84 mmol)3-(2,4-Dichloropyridin-3-ylmethyl)-3-hydroxy-1-azabicyclo[2.2.2]octaneN-borane complex and 319 mg (7.97 mmol) of sodium hydride indimethylformamide as in Preparation 2. This mixture was treated withaqueous hydrobromic acid in acetone to provide, following flashchromatography on neutral silica gel using a mixture of 98:2 ammoniatedchloroform/methanol, 559 mg of4′-chlorospiro[1azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine],m.p. 109-110° C. (ethyl ether), and 463 mg of4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[3,2-c]pyridine],m.p. 113-115° C.

Example 34 Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[3,2-c]pyrdine]

The4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[3,2-c]pyridine](125 mg or 5.0 mmol) from Example 33 was dissolved in 50 mL of anhydrousmethanol, and 25 mg of 10% palladium on carbon was added. The bottle wasplaced on the Parr apparatus under hydrogen atmosphere and shaken for2.5 hours. The Pd/C was removed by filtration and washed with methanol.The solvent was removed in vacuo and the residue was taken up inchloroform and methanol and transferred to a vial. The solvent wasremoved in vacuo and chased with two portions of ether. After dryingwith high vacuum obtained 112 mg of off-white powder (104% with residualsolvent.) Electrospray MS 217 [MH]⁺.

Example 354′-Methoxyspiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Sodium hydride (241 mg, 6.0 mmol) was added to a solution of 76 mg (0.30mmol) of4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]in 25 mL of ice-cold methanol, under a nitrogen atmosphere. Theresulting solution was heated to reflux and stirred for 4 days, thencooled to ambient temperature, poured into 30 mL of water, and extractedwith chloroform (3×30 mL). The combined organic extract was dried overanhydrous magnesium sulfate, concentrated in vacuo and the residue flashchromatographed on neutral silica gel using a 9:1 mixture of ammoniatedchloroform/methanol to give 50 mg (67%) of the title compound as a whitesolid: electrospray MS (m/z, relative intensity) 247 ([MH]⁺).

Example 364′-Phenylthiospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

Sodium hydride (151 mg, 3.77 mmol) was added to a solution of 97 mg(0.387 mmol) of4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine],0.40 mL (3.91 mmol) of thiophenol and 0.10 mL of methanol in 15 mL ofdioxane, under a nitrogen atmosphere. The reaction was refluxed for 4days, cooled to ambient temperature, diluted with 30 mL of water, andextracted with chloroform (3×30 mL). The combined organic extract wasdried over anhydrous magnesium sulfate, concentrated in vacuo and theresidue flash chromatographed on neutral silica gel using a 98:2 mixtureof ammoniated chloroforn/methanol to give 65 mg (52%) of the titlecompound as a colourless oil: electrospray MS (m/z, relative intensity)325 ([MH]⁺).

Example 374′-(N-2-Aminoethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

A solution of 74 mg (0.295 mmol) of4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]in 10 mL of ethylenediamine was heated to reflux under a nitrogenatmosphere and stirred for 4 days. Upon cooling to ambient temperature,the solvent was removed in vacuo. The residue was dissolved in 20 mL ofsaturated aqueous sodium carbonate and extracted with chloroform (3×25mL). The combined organic extract was dried over anhydrous magnesiumsulfate and concentrated in vacuo to give the title compound as a darkoil, 80 mg (100%): electrospray MS (m/z, relative intensity) 275([MH]⁺).

Example 384′-(4-N-Methylpiperazin-1-yl)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

A solution of 97 mg (0.387 mmol) of4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]in 1 mL of 1-methylpiperazine was heated to reflux under a nitrogenatmosphere and stirred for 18 hours. Upon cooling to ambienttemperature, the diluted with 40 mL of water, basicified with 2 mL ofsaturated aqueous sodium carbonate and extracted with chloroform (3×25mL). The combined organic extract was dried over anhydrous magnesiumsulfate, concentrated in vacuo, and flash chromatographed on neutralsilica gel using a 4:1 mixture of ammoniated chloroform/methanol toprovide 59 mg (48%) of the title compound as an amber oil: electrosprayMS (m/z, relative intensity) 315 ([MH]⁺).

Example 394′-(Phenylmethyl)aminospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

A solution of 97 mg (0.387 mmol) of4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]in 5 mL of benzylamnine was heated to reflux under a nitrogen atmosphereand stirred for 18 hours. Upon cooling to ambient temperature, thediluted with 40 mL of water, basicified with 2 mL of saturated aqueoussodium carbonate and extracted with chloroform (3×25 mL). The combinedorganic extract was dried over anhydrous magnesium sulfate, concentratedin vacuo, and flash chromatographed on neutral silica gel using a 9:1mixture of ammoniated chloroform/methanol to provide 42 mg (34%) of thetitle compound as a white solid: electrospray MS (m/z, relativeintensity) 322 ([MH]⁺).

Example 404′-(Methylamino)spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

A solution of 151 mg (0.60 mmol) of4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]in 25 mL of 40% aqueous methylanrine was heated to 175° C. in a steelbomb for 18 hours, then cooled to ambient temperature and concentratedin vacuo. The residue was dissolved in 10 mL of ethanol containing 0.4mL of concentrated hydrochloric acid and the solution was allowed tostand overnight. After filtering, the solution was concentrated in vacuoand the residue crystallized from isopropanol, giving 147 mg of thetitle compound as a white solid: electrospray MS (m/z, relativeintensity) 246 ([MH]⁺).

Example 41Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine-7′-oxide]

A solution ofspiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine] (2.88 g,13.3 mmol) and aqueous hydrogen peroxide (30%, 5 ml) in acetic acid (20ml) was heated under reflux. After 16 h and 24 h, further portions ofhydrogen peroxide were added, and heating was continued for a total of48 h. The solution was then evaporated, then the residue was redissolvedin ethanol (40 ml) which had been saturated with sulfur dioxide. After 4h the solution was evaporated and the residue was purified by HPLC onsilica using as the eluant a 0-50% gradient of a mixture of solvents (7M methanolic ammonia (25%) methanol (25%) chloroform (50%)) andchloroform. The title compound (934 mg, 4.0 mmol, 30%) was a solid: DCIMS 233 ([MH]⁺).

Example 42Spiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine-6′-carbonitrile]

A solution ofspiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine-7′-oxide]95 mg, 0.41 mmol) was dissolved in acetonitrile (2 ml). Triethylamine(0.12 ml, 87 mg, 0.86 mmol), and then trimethylsilyl cyanide (0.2 ml,149 mg, 1.5 mmol) were added. The solution was stirred at roomtemperature overnight, then heated to reflux temperature. After approx.8 h, further trimethylsilyl cyanide (0.2 ml) was added. After heatingunder reflux overnight the solution was allowed to cool. Excess methanolwas added, and the solution was left at room temperature for 4 h thenevaporated. The residue was purified by HPLC on silica using as theeluant a 0-25% gradient of a mixture of solvents (7 M methanolic ammonia(25%) methanol (25%) chloroform (50%)) and chloroform. The titlecompound (50 mg, 0.21 mmol, 51%) was a solid: electrospray MS 242([MH]⁺).

Example 436′-Chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

A solution ofspiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine-7′-oxide](98 mg, 0.42 mmol) in phosphorous oxychloride (2 ml) was heated underreflux for 2 h. The solution was evaporated, the residue was partitionedbetween aqueous potassium carbonate and chloroform, then the organiclayer was dried (magnesium sulfate), filtered, and evaporated. Theresidue was purified by HPLC on silica using as the eluant a 0-25%gradient of a mixture of solvents (7M methanolic ammonia (25%) methanol(25%) chloroform (50%)) and chloroform. The title compound (26 mg, 0.10mmol, 25%) was a solid: electrospray MS 251 ([MH]⁺ with ³⁵Cl) and 253([MH]⁺with ³⁷Cl).

Example 446′-Fluorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](a)6′-Fluorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]N-borane complex

A solution of phenyllithium (1.8 M in cyclohexane, 13.5 mL) was added toTHF (15 mL) under argon. Diisopropylamine (0.5 mL) was added, and thesolution was cooled to −78° C. (dry ice/acetone bath temperature). Tothe resulting solution, 2,6-difluoropyridine (1.23 mL, 1.56 g, 13.6mmol) was added dropwise, then after 1 h, a solution ofspiro[1-azabicyclo[2.2.2]octane-3,2′-oxirane] N-borane complex (765 mg,5.0 mmol) in tetrahydrofuran was added dropwise. The solution wasstirred at −78° C. for 1 h and the cooling bath was then replaced with adry ice/acetonitrile bath. The solution was then stirred overnight,warming to room temperature. Saturated aqueous sodium bicarbonate wasadded, and the solution was then extracted with chloroform. The extractwas then dried (MgSO₄), filtered, and evaporated. The residue wasdissolved in DMF (20 mL), and was then added to a suspension ofhexane-washed sodium hydride (60% mixture with mineral oil, 507 mg, 12.7mmol) in DMF (20 mL) stirred at 0° C. The solution was stirredovernight, warming to room temperature. Saturated aqueous sodiumbicarbonate was added to the solution, which was then extracted withchloroform. The extract was then dried (MgSO₄), filtered, andevaporated, and the residue was purified by HPLC using a gradient of5-50% ethyl acetate and hexane to give the sub-title compound (102 mg,8%, 0.41 mmol): electrospray MS (m/z) 247 [M−H]⁺.

(b)6′-Fluorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]

6′-Fluorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine]N-borane complex (98 mg, 0.40 mmol) was dissolved in acetone (5 ml). 48%Aqueous hydrobromic acid (2 ml) was diluted with water (2 ml) and thenwas added to the solution. The resulting mixture was stirred at roomtemperature overnight. The solution was then evaporated and partitionedbetween aqueous sodium carbonate and chloroform. The organic extract wasthen dried (MgSO₄), filtered, and evaporated, and the residue waspurified by HPLC using a gradient of 0-25% 1:1:2 7M methanolicammonia:methanol:chloroform and chloroform to give the title compound(39 mg, 0.168 mmol, 43%) as a solid: electrospray MS (m/z relativeintensity) 235 ([MH]⁺, 100).

What is claimed is:
 1. A compound of the formula

wherein n is 0 or 1; m is 0 or 1; p is 0 or 1; X is oxygen or sulfur; Wis oxygen, H₂ or F₂; A is N or C(R²); G is N or C(R³); D is N or C(R⁴);with the proviso that no more than one of A, G, and D is nitrogen; R¹ ishydrogen or C₁ to C₄ alkyl; R², R³, and R⁴ are independently hydrogen,halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, aryl, heteroaryl,OH, OC₁-C₄ alkyl, CO₂R¹, —CN, —NO₂, —NR⁵R⁶, —CF₃, —OSO₂CF₃ or R² and R³,or R³ and R⁴, respectively, may together form another six memberedaromatic or heteroaromatic ring sharing A and G, or G and D,respectively, containing between zero and two nitrogen atoms, andsubstituted with one to two of the following substituents: independentlyhydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, aryl,heteroaryl, OH, OC₁-C₄ alkyl, CO₂R¹, —CN, —NO₂, —NR⁵R⁶, —CF₃, —OSO₂CF₃;R⁵ and R⁶ are independently hydrogen, C₁-C₄ alkyl, C(O)R⁷, C(O)NHR⁸,C(O)OR⁹, SO₂R¹⁰ or may together be (CH₂)_(j)Q(CH₂)_(k) where Q is O, S,NR¹¹, or a bond; j is 2 to 7; k is 0 to 2; R⁷, R⁸, R⁹, R¹⁰, and R¹¹ areindependently C₁-C₄ alkyl, aryl, or heteroaryl; or an enantiomerthereof.